Synaptic damage has been described with both HIV dementia (HIVD) and METH use. For example, dendritic injury has been well described in HIV encephalitis (HIVE), and METH using patients with HIV encephalitis (HIVE) show greater loss of synaptic protein immunoreactivity than do HIVE non-METH users. Matrix metalloproteinases (MMPs) are zinc dependent enzymes whose levels may be substantially elevated in association with HIVE. Further both HIV proteins and methamphetamine have been shown to increase MMP release from cultured neurons and glia. Though well studied for their effects outside of the brain, studies of MMPs in the CNS have generally been limited to their effects on proteins of the blood brain barrier. Of particular interest, however, is the potential for MMPs to target proteins critical to synaptic structure and function. In vitro studies, often using non-neural systems, have shown that MMPs target molecules including syndecans, cadherins, and SIRP-1a. Of interest, each of these molecules is known to play a role in synaptic adhesion. Moreover, as will be shown to follow, we have preliminary data which suggests that select MMPs target molecules that play a predominant role in synaptic function. One such molecule is the NR1 subunit of the NMDA type glutamate receptor. The present application will therefore outline plans to test the hypothesis that MMPs are critical mediators of synaptic injury occurring with HIV proteins and METH. Dissociated and slice cultures will be treated with HIV proteins and METH, in the presence or absence of specific MMP inhibitors, and then evaluated for evidence of MMP mediated synaptic injury. MMP levels, select synaptic adhesion molecules, and NMDA receptor subunits will be examined, as will be neuronal death. Synaptic structure will also be evaluated by confocal and electron microscopy. In parallel studies, METH treated mice that over express HIV-1 Tat or gp120 will be treated with a broad spectrum MMP inhibitor, or vehicle control, and CNS tissues will be similarly evaluated. The results of the studies proposed in this R21 application should determine whether MMPs are elevated in HIV protein/METH treated cultures and animals. More importantly, the proposed studies should determine whether MMPs likely play a role in synaptic injury occurring with METH use and HIV infection, and whether general or selective MMP antagonists should be considered for the treatment of specific patients. [unreadable] [unreadable] [unreadable]